Antithrombotic substituted cycloalkano (B) dihydroindole sulphonamides

ABSTRACT

Substituted antithrombotic substituted cycloalkano[b]dihydroindole- and -indole-sulphonamides for treatment of thromboses, thromboembolisms, ischaemias, asthma and allergies, of the formula ##STR1## in which R 1 , R 2 , R 3  and R 4  are hydrogen or other radicals, 
     X is aryl, alkyl or CF 3 , 
     m and Z each is 1,2,3 or 4, 
     n is 0,1 or 2, 
     A is a bond or --NH--, and 
     Y is OH, alkoxy, aryloxy, amino or sulphonylamine, 
     with the proviso, that in all cases, two of the substituents R 1  -R 4  are other than hydrogen in the event that m represents the number 2 and Y represents the hydroxyl group, or a salt thereof.

This application is a continuation of application Ser. No. 786,478,filed Nov. 1, 1991, abandoned, which is a division of Ser. No. 678,563,filed Mar. 28, 1991, now U.S. Pat. No. 5,096,897.

The invention relates to substituted cycloalkano[b]dihydroindole- and-indole-sulphonamides, to processes for their preparation, and to theiruse in medicaments.

It is already known thatcycloalkano[b]dihydroindole-and-indole-sulphonamides are active asinhibitors of thrombocyte aggregation [cf. DOS (German PublishedSpecification) 3,631,824].

Substituted cycloalkano[b]dihydroindole-and-indolesulphonamnides of thegeneral formula (I) have now been found ##STR2## in which formula R¹,R², R³ and R⁴ are identical or different and

represent hydrogen, nitro, cyano, halogen, trifluoromethyl, carboxyl,hydroxyl or trifluoromethoxy, or

represent a group of the formula --S(O)_(w) R⁵ where

R⁵ --represents straight-chain or branched alkyl having up to 8 carbonatoms or represents aryl which has 6 to 10 carbon atoms and which, inturn, is substituted by halogen, nitro, cyano or trifluoromethyl and

w--represents a number 0, 1 or 2, or represent straight-chain orbranched alkoxy or alkoxycarbonyl, each of which has up to 10 carbonatoms, or represent benzyloxy, or

represent a group of the formula --NR⁶ R⁷ where

R⁶ and R⁷ are identical or different and

represent hydrogen, straight-chain or branched alkyl or acyl, each ofwhich has up to 8 carbon atoms, or

represent aryl having 6 to 10 carbon atoms, or

represent cycloalkyl having 3 to 8 carbon atoms or

represent aryl having 6 to 10 carbon atoms, or

represent straight-chain or branched alkyl or alkenyl, each of which hasup to 10 carbon atoms and each of which is optionally substituted byhalogen, hydroxyl, carboxyl, cyano, aryl having 6 to 10 carbon atoms,straight-chain or branched alkyl, alkoxy or alkoxycarbonyl, each ofwhich has up to 8 carbon atoms, or by a group of the formula ##STR3##where w, R⁵, R⁶ and R⁷ have the abovementioned meanings, X--representsaryl which has 6 to 10 carbon atoms and which can optionally be up topentasubstituted by identical or different substituents from the seriescomprising nitro, halogen, cyano, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, hydroxyl, carboxyl, aryl or aryloxy having 6 to 10carbon atoms, and straight-chain or branched alkoxy or alkoxycarbonyl,each of which has up to 8 carbon atoms, or by straight-chain or branchedalkyl which has up to 8 carbon atoms and which, in turn, can besubstituted by carboxyl, hydroxyl, alkoxycarbonyl having up to 6 carbonatoms or aryl having 6 to 10 carbon atoms, or by a group of the formula--S(O)_(w) R⁵ or --NR⁶ R⁷, where

w, R⁵, R⁶ and R⁷ have the abovementioned meanings, or

represents a straight-chain or branched alkyl having up to 8 carbonatoms or

represents trifluoromethyl,

m--represents the number 1, 2, 3 or 4,

n--represents the number 0, 1 or 2,

z--represents the number 1, 2, 3 or 4,

A--represents a bond or the --NH group, and

Y--represents hydroxyl, alkoxy having up to 8 carbon atoms, aryloxyhaving 6 to 10 carbon atoms or the group --NR⁶ R⁷ where

R⁶ and R⁷ have the abovementioned meanings, or

represents a group of the formula --NH--SO₂ --R⁵ where

R⁵ --has the abovementioned meaning,

with the proviso that, in all cases, two of the substituents R¹ --R⁴ areother than hydrogen in the event that m represents the number 2 and Yrepresents the hydroxyl group, if appropriate in an isomeric form, andsalts of these compounds.

The substituted cycloalkano[b]dihydroindole- and -indolesulphonamidesaccording to the invention have one or more asymmetric carbon atoms andcan therefore exist in various stereochemical forms. It is also possiblefor regioisomers to occur. The individual isomers and mixtures thereofare all a subject of the invention.

The compounds according to the invention exist in stereoisomeric formswhich are either like image and mirror-image (enantiomers) or not likeimage and mirror-image (diastereomers). The invention relates to theantipodes and to the racemic forms and to the mixtures of diastereomers.The racemic forms, like the diastereomers, can be separated in a knownmanner to give the stereoisomerically uniform constituents (cf. E. L.Eliel, Stereo-chemistry of Carbon Compounds, McGraw Hill, 1962). Whatfollows are examples of isomeric forms of thecycloalkano[b]dihydroindole- and -indole-sulphonamides:

a) Cycloalkano[b]indole-sulphonamides ##STR4## b)Cycloalkano[b]dihydroindolesulphonamides ##STR5## where R¹, R², R³, R⁴,A, X, Y, m, n and z have the above-mentioned meanings.

The substituted cycloalkano[b]dihydroindole- and -indole-sulphonamidesaccording to the invention can also be in the form of their salts. Saltswhich may be mentioned in general in this connection are salts withorganic or inorganic bases.

Physiologically tolerable salts are preferred within the scope of thepresent invention. Physiologically tolerable salts of the substitutedcycloalkano[b]-dihydroindole- and -indole-sulphonamides can be metalsalts or ammonium salts of the substances according to the inventionwhich have a free carboxyl group. Examples of particularly preferredsalts are sodium, potassium, magnesium or calcium salts and ammoniumsalts which are derived from ammonia or organic amines, such as, forexample, ethylamine, di- or triethylamine, di- or tri-ethanolamine,dicyclohexylamine, dimethylaminoethanol, arginine, lysine orethylenediamine.

Surprisingly, the substances according to the invention are active asinhibitors of thrombocyte aggregation, furthermore cause inhibition ofthromboxane synthase on isolated platelets, and can be used fortherapeutic treatments of humans and animals.

Preferred compounds of the general formula (I) are those in which

R¹, R², R³ and R⁴ are identical or different and

represent hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano,trifluoromethyl, carboxyl, hydroxyl or trifluoromethoxy, or

represent a group of the formula --S(O)_(w) R⁵ where

R⁵ --represents straight-chain or branched alkyl having up to 6 carbonatoms, or represents phenyl which, in turn, can be substituted byfluorine, chlorine, bromine, nitro, cyano or trifluoromethyl,

w--represents a number 0, 1 or 2,

represent straight-chain or branched alkoxy or alkoxycarbonyl, each ofwhich has up to 8 carbon atoms, or

represent a group of the formula --NR⁶ R⁷ where

R⁶ and R⁷ are identical or different and denote hydrogen, straight-chainor branched alkyl having up to 6 carbon atoms or phenyl or

represent cyclopropyl, cyclopentyl, cyclohexyl or phenyl, or

represent straight-chain or branched alkyl or alkenyl, each of which hasup to 8 carbon atoms, and each of which is optionally substituted byfluorine, chlorine, bromine, hydroxyl, carboxyl, cyano, phenyl,straight-chain or branched alkyl, alkoxy or alkoxycarbonyl, each ofwhich has up to 6 carbon atoms, or by a group of the formula --S(O)_(w)R⁵ or --NR⁶ R⁷ where

w, R⁵, R.sup. 6 and R⁷ have the abovementioned meanings,

X--represents phenyl which can optionally be up to tetrasubstituted byidentical or different substituents from the series comprising nitro,hydroxyl, fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl,trifluoromethoxy, hydroxyl, carboxyl, phenyl, phenoxy, straight-chain orbranched alkoxy or alkoxycarbonyl, each of which has up to 6 carbonatoms, or by straight-chain or branched alkyl having up to 6 carbonatoms, or

represents straight-chain or branched alkyl having up to 6 carbon atomsor trifluoromethyl,

m--represents the number 1, 2, 3 or 4,

n--represents the number 0 or 1,

z--represents the number 1, 2 or 3,

A--represents a direct bond or the --NH group, and

Y--represents hydroxyl, alkoxy having up to 6 carbon atoms, phenoxy orthe group --NR⁶ R⁷, where R⁶ and R⁷ have the abovementioned meanings, or

represents a group of the formula --NHSO₂ --R⁵ where

R⁵ --has the abovementioned meaning,

with the proviso that, in all cases, two of the substituents R¹ --R⁴ areother than hydrogen in the event that m denotes the number 2 and Yrepresents the hydroxyl group, if appropriate in an isomeric form, andsalts of these compounds.

Particularly preferred compounds of the general formula (I) are those inwhich

R¹, R², R³ and R⁴ are identical or different and

represent hydrogen, fluorine or chlorine,

represent a group of the formula --S(O)_(w) --R⁵ where

R⁵ --represents straight-chain or branched alkyl having up to 4 carbonatoms, or represents phenyl which, in turn, can be substituted byfluorine, chlorine or bromine and

w--denotes the number 2,

represent straight-chain or branched alkoxy or alkoxycarbonyl, each ofwhich has up to 4 carbon atoms,

represent the group of the formula --NR⁶ R⁷ where

R⁶ and R⁷ are identical or different and

denote hydrogen, straight-chain or branched alkyl having up to 4 carbonatoms or phenyl, or

represent straight-chain or branched alkyl having up to 6 carbon atomswhich is optionally substituted by fluorine, chlorine, bromine,hydroxyl, cyano or phenyl,

X--represents phenyl which is optionally up to trisubstituted byidentical or different substituents from the series comprising fluorine,chlorine, bromine, cyano, trifluoromethyl, trifluoromethoxy or bystraight-chain or branched alkyl, alkoxy and alkoxycarbonyl, each ofwhich has up to 4 carbon atoms,

m--represents the number 1, 2, 3 or 4,

n--represents the number 0 or 1,

z--represents the number 1 or 2,

A--represents the --NH group, and

Y--represents hydroxyl, alkoxy having up to 4 carbon atoms, phenoxy orthe group of the formula --NR⁶ R⁷ where

R⁶ and R⁷ have the abovementioned meanings, or

represents a group of the formula --NHSO₂ --R⁵ where

R⁵ has the abovementioned meaning, with the proviso that, in all cases,two of the substituents R¹ --R⁴ are other than hydrogen in the eventthat m denotes the number 2 and Y represents the hydroxyl group, ifappropriate in an isomeric form, and salts of these compounds.

The compounds of the general formula (I) can be prepared

[A] by reacting compounds of the general formula (VIII) ##STR6## inwhich R¹, R², R³, R⁴, n, z, A and X have the abovementioned meanings, inthe event that m represents the number 2, by initially reactingacrylonitrile in inert solvents, if appropriate in the presence of abase, to give the corresponding cyanoethyl compounds and thenhydrolyzing these compounds to give the corresponding acids (Y═OH), or

[B] by reacting compounds of the general formula (IX) ##STR7## in whichR¹, R², R³, R⁴ and m have the abovementioned meanings and

Y'--represents (C₁ --C₄)-alkoxycarbonyl or cyano, withcycloalkanonesulphonamides of the general formula (X) ##STR8## in whichz, n, A and X have the abovementioned meanings, in inert solvents, ifappropriate in the presence of a catalyst, and furthermore, in the caseof the acids (Y═OH), hydrolyzing the esters by a conventional method, inthe case of variation of the esters (Y=alkoxy, C₁ -C₈ -phenoxy),reacting the acids with the corresponding alcohols in the presence of acatalyst by a customary method, if appropriate in inert solvents, in thecase of the amides and sulphonamides (Y=--NR⁶ R⁷, --NHSO₂ --R⁵),reacting either the esters directly, or the acids thereof byconventional activation, with the amines or sulphonamides of the generalformulae (XIa) and (XIb)

    HNR.sup.6 R.sup.7                                          (XIa)

    NH.sub.2 --SO.sub.2 --R.sup.5                              (XIb)

in which

R⁵, R⁶ and R⁷ have the abovementioned meanings, if appropriate in thepresence of a catalyst, in the case of thecycloalkano[b]dihydroindolesulphonamides, reducing thecycloalkano[b]indolesulphonamides in the presence of a reducing agent ininert solvents, separating the isomers, if appropriate, and in the caseof salt formation, reacting the product with a suitable base.

The process according to the invention can be illustrated for example bythe following equation:

[A] ##STR9## [B] ##STR10##

Solvents which can be used for processes [A] and [B] according to theinvention are water and organic solvents which do not undergo changesunder the reaction conditions. These preferably include chlorinatedhydrocarbons, such as, for example, chloroform or methylene chloride,alcohols, such as methanol, ethanol, propanol or isopropanol, ethers,such as diethyl ether, tetrahydrofuran, dioxane, glycol monomethyl etheror glycol dimethyl ether, hydrocarbons, such as benzene, toluene,xylene, cyclohexane, hexane or mineral oil fractions,dimethylsulphoxide, dimethylformamide, hexamethylphosphoric triamide,ethyl acetate, acetonitrile or pyridine. It is also possible to usemixtures of the solvents mentioned.

Bases which can be used for processes [A] and [B] according to theinvention are customary basic compounds. These preferably include alkalimetal hydroxides and alkaline earth metal hydroxides, such as lithiumhydroxide, sodium hydroxide, potassium hydroxide or barium hydroxide,alkali metal hydrides, such as sodium hydride, alkali metal carbonatesor alkaline earth metal carbonates, such as sodium carbonate orpotassium carbonate, or alkali metal alkoxides, such as, for example,sodium methoxide, sodium ethoxide, potassium methoxide, potassiumethoxide or potassium tert. -butoxide, or amides, such as sodium amideor lithium diisopropylamide, or organic amines or ammonium salts, suchas benzyltrimethylammonium hydroxide, tetrabutylammonium hydroxide,pyridine, triethylamine or N-methylpiperidine.

Processes [A] and [B] according to the invention are generally carriedout in a temperature range of 0° C. to 150° C., preferably of 0° C. to100° C.

Processes [A] and [B] are generally carried out under atmosphericpressure. However, it is also possible to carry out the processes in avacuum or under super-atmospheric pressure (for example from 0.5 to 5bar).

The esters are hydrolyzed by a customary method, by treating the estersin inert solvents with customary bases, it being possible to convert theinitially resulting salts into the free carboxylic acids by treatingthem with acid.

Bases which are suitable for the hydrolysis are the customary inorganicbases. These preferably include alkali metal hydroxides or alkalineearth metal hydroxides, such as, for example, sodium hydroxide,potassium hydroxide or barium hydroxide, or alkali metal carbonates,such as sodium carbonate or potassium carbonate.

Solvents which are suitable for the hydrolysis are water or the organicsolvents which are customary for hydrolysis. These preferably includealcohols, such as methanol, ethanol, propanol, isopropanol or butanol,or ethers, such as tetrahydrofuran or dioxane, or dimethylformamide ordimethyl sulphoxide. Solvents which are particularly preferably used arealcohols, such as methanol, ethanol, propanol or isopropanol. It is alsopossible to employ mixtures of the solvents mentioned.

The hydrolysis is generally carried out within a temperature range of 0°C. to +140° C., preferably of +20° C. to +100° C.

The hydrolysis is generally carried out under atmospheric pressure.However, it is also possible to carry out the hydrolysis in a vacuum orunder super-atmospheric pressure (for example from 0.5 to 5 bar).

When carrying out the hydrolysis, the base is generally employed in anamount of 1 to 5 moles, preferably of 1 to 2 moles, based on 1 mole ofthe ester. It is particularly preferred to use molar amounts of thereactants.

When the reaction is carried out, the first step gives the salt of thecompounds according to the invention as intermediates which can beisolated. The acids according to the invention are obtained by treatingthe salts with customary inorganic acids. These preferably includemineral acids, such as, for example, hydrochloric acid, hydrobromicacid, sulphuric acid or phosphoric acid. In connection with thepreparation of the carboxylic acids, it has proven advantageous toacidify the basic reaction mixture of the hydrolysis reaction in asecond step without the salts being isolated. The acids can then beisolated in a customary manner.

The acids are esterified by a customary method, by reacting the acidswith the appropriate alcohols in the presence of a catalyst and, ifappropriate, in one of the abovementioned solvents. It is preferred toemploy this alcohol also as the solvent.

Catalysts which can be employed are inorganic acids, such as, forexample, sulphuric acid or inorganic acid chlorides, such as, forexample, thionyl chloride.

In general, 0.01 to 1, preferably 0.05 to 0.5, mole of catalyst areemployed per mole of reactant.

The amidation is carried out in one of the above-mentioned solvents,preferably in alcohols, such as ethanol or methanol, within atemperature range of 0° C. to +50° C., preferably of +10° to +30° C.,and under atmospheric pressure.

If appropriate, both the esterification and the amidation (Y═NR⁶ R⁷,--NHS0₂ R⁵) can proceed via the activated step of the acid halides (I,Y=halogen), which can be prepared from the corresponding acid byreaction with thionyl chloride, phosphorus trichloride, phosphoruspentachloride, phosphorus tribromide or oxalyl chloride.

The amidation with the sulphonamides of the general formula (XIb) canalso proceed via the step of the acids (R, Y=OH) in the presence ofcondensation agents, such as, for example, N,N'-dicyclohexylcarbodiimide, or by activation, for example, by reactionto form the corresponding imidazolides, according to customary methods.

Some of the compounds of the general formula (VIII) are new. They can beprepared by reacting phenylhydrazines of the general formula (XII)##STR11## in which R¹ R², R³ and R⁴ have the abovementioned meanings,with cycloalkanonesulphonamides of the general formula (X) ##STR12## inwhich A, X, n and z have the abovementioned meanings, in the presence ofthe abovementioned inert solvents and if appropriate in the presence ofa catalyst.

The reaction with phenylhydrazines of the formula (XII) proceeds underthe reaction conditions described in the case of process (B).

Examples of hydrazines which are employed in the process according tothe invention are: phenylhydrazine, 4-methoxyphenylhydrazine,4-chlorophenylhydrazine, 4-fluorophenylhydrazine,4-methylphenylhydrazine, 2,4-difluorophenylhydrazine,3,5-difluorophenylhydrazine, 3-fluorophenylhydrazine and2-fluorophenylhydrazine.

Some of the phenylhydrazines of the general formula (XII) are known orcan be prepared by a customary method [cf. Houben-Weyl, "Methoden derorganischen Chemie [Methods in Organic Chemistry]", X/2, page 1, 123,693].

The cycloalkanonesulphonamides of the general formula (X) and theirpreparation are known [cf. DOS (German Published Specification)3,631,824].

The pure enantiomeric compounds of the general formula (I) according tothe invention can be obtained by customary methods, e.g. analogously tothe process described in DOS (German Published Specification) 3,631,824.

The compounds of the general formula (IX) are known per se or can beprepared by a customary method [cf. DOS (German Published Specification)2,312,256].

The amines of the general formula (XIa) are known [cf. Houben-Weyl,"Methoden der organischen Chemie [Methods in Organic Chemistry]",Volumes XI/1 and XI/2].

The sulphonamides of the general formula (XIb) are likewise known [cf.Beilstein, 11, 26].

The substituted cycloalkano[b]indole- and -dihydroindlesulphonamides ortheir salts can be employed as active compounds in medicaments. Theactive compounds are active as inhibitors of thrombocyte aggregation andas thromboxane A₂ -antagonists, and they cause inhibition of thromboxanesynthase on isolated platelets. They can preferably be employed in thetreatment of thromboses, thromboembolisms and ischaemias, and in theprophylaxis of myocardial infarct as antiasthmatics and antiallergics.

To determine the action as an inhibitor of thrombocyte aggregation,blood was used from healthy subjects of both sexes. 9 parts of bloodwere treated with one part of 3.8% strength aqueous sodium citratesolution as an anticoagulant. From this blood, platelet-rich citratedplasma (PRP)¹ is obtained (Jurgens/Beller, Klinische Methoden derBlutgerinnungsanalyse [Clinical Methods in Blood Coagulation Analysis];Thieme Verlag, Stuttgart, 1959).

For these assays, 0.8 ml of(PRP)¹ and 0.1 ml of the active compoundsolution were preincubated at 37° C. in a water bath. The thrombocyteaggregation was then determined in an aggregometer at 37° C.(Therapeutische Berichte 47, 80-86, 1975) by means of turbidometry(Born, G. V. R., J. Physiol. (London), 162, 67, 1962). For this purpose,the preincubated sample was treated with 0.1 ml of collagen, an agentwhich triggers aggregations. The(PRP)¹ sample underwent changes inoptical density, which was recorded during a period of 6 minutes, andthe response was determined after 6 minutes. From this, the inhibitioncompared with the control is calculated as a percentage. The limitingconcentration given is the range of the minimum effective concentration.

The limiting concentrations are between 0.01 and 10 mg/l.

    ______________________________________                                        Example No.    EC in mg/l                                                     ______________________________________                                        4              0.01-0.03                                                      8              0.3-1.0                                                        15             0.01-0.03                                                      ______________________________________                                    

Measurement of thromboxane synthase on washed human thrombocytes

1. Preparation of thrombocyte suspensions

Blood from healthy donors is taken up in EDTA (1% strength in 0.9% NaCl,9+1), and the mixture is centrifuged for 20 minutes at 1,000 rpm (150g). The platelet-rich plasma (PRP)² is pipetted off, and 10 ml batchesare centrifuged for 20 minutes at 2,500 rpm. The platelet-rich plasma²is decanted off.

The remaining platelets are suspended in 5 ml of resuspension buffer(0.15M TRIS/0.9% of NaCl/77 mmol EDTA, 8:91:1; pH 7.4 set using 1N HCl),the suspension is centrifuged for 20 minutes at 2,500 rpm and suspendedin 1 ml of resuspension buffer. A thrombocyte titer of 3×10⁵ /μl isestablished.

2. Measurement of thromboxane synthase

1 ml of the platelet suspension and 0.01 ml of the test preparation in a10% strength DMSO solution are incubated for 2 minutes at 37° C. To thisis added 0.1 ml of ³ H-arachidonic acid Amersham Buchler GmbH and Co. KG(6.6×10⁻⁵ mol/l) of a specific activity of 140 MBq/mmol, and incubationis continued at 37° C. for 10 minutes. After the reaction, the mixtureis acidified using about 0.02 ml of 0.5N citric acid and immediatelyextracted 3 times using 1 ml of ethyl acetate each time. The supernantsare collected in 10 ml glass tubes, and the ethyl acetate is removed byblowing in N₂ at 25° C. The residue is taken up in 50 μl of MeOH/CHCl₃(1:1) and the fluid is applied to TLC glass plates (Silica gel 60 F25420×20 cm, by Merck).

The separation is performed in a mobile phase mixture CHCl₃/MeOH/glacial acetic acid/H₂ O (80:8:1:0.8). The radioactivedistribution is recorded in a TLC scanner Ramona-Ls, made by Raytest,and evaluated quantitatively using an integration programme.

The concentration of test substances which lead to a 50% inhibition ofthromboxane formation, compared with the control, is determined.

Inhibition of thromboxane synthesis on washed platelets from humanblood.

    ______________________________________                                        Example No.    IC.sub.50 mol/l                                                ______________________________________                                        4              1-3 × 10.sup.-6                                          ______________________________________                                    

The novel active compounds can be converted in a manner known per seinto the customary formulations, such as tablets, capsules, coatedtablets, pills, granules, aerosols, syrups, emulsions, suspensions andsolutions, with inert non-toxic, pharmaceutically acceptable excipientsor solvents being used. In this connection, the therapeutically activecompound should be present in each case in a concentration of about 0.5to 90% by weight, preferably of 5 to 70% by weight, based on thepreparation, which is sufficient to achieve the stated dosage range.

For example, the formulations are prepared by extending the activecompounds with solvents and/or excipients, if appropriate with the useof emulsifiers and/or dispersants, it being possible, for example whenwater is used as the diluent, to use organic solvents as auxiliarysolvents, if necessary.

Examples of auxiliaries which may be mentioned are: water, non-toxicorganic solvents, such as paraffins (for example mineral oil fractions),vegetable oils (for example groundnut/sesame seed oil), alcohols (forexample ethyl alcohol, glycerol), glycols (for example propylene glycol,propylethylene glycol), solid excipients, such as, for example, groundnatural rocks (for example kaolins, clays, talc, chalk), groundsynthetic rocks (for example highly-disperse silica, silicates), sugars(for example sucrose, lactose and fructose), emulsifiers (for examplepolyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers,alkylsulphonates and arylsulphonates), dispersants (for example lignin,sulphite wet liquors, methylcellulose, starch and polyvinylpyrrolidone)and lubricants (for example magnesium stearate, talc, stearic acid andsodium laurylsulphate).

The application can be carried out in a customary manner, preferablyorally or parenterally, in particular perlingually or intravenously. Inthe case of oral application, tablets can, of course, also containadditives, such as sodium citrate, calcium carbonate and dicalciumphosphate together with various adjuvants, such as starch, preferablypotato starch, gelatin, etc., besides the excipients mentioned.Lubricants, such as magnesium stearate, sodium laurylsulphate and talccan furthermore be used for tablet-making. In the case of aqueoussuspensions and/or elixirs which are intended for oral administration,it is possible to add various flavor improvers or colorants to theactive substances, in addition to the abovementioned auxiliaries.

In the case of parenteral administration, active compound solutions canbe employed using suitable liquid excipients.

In general, it has proven advantageous to administer amounts of about0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg, of body weight toachieve effective results on intravenous administration. In the case oforal administration, the dosage is generally about 0.01 to 20 mg/kg,preferably 0.1 to 10 mg/kg, of body weight.

However, occasionally it can be advantageous to deviate from the figuresmentioned, and to do so as a function of the body weight or the type ofadministration route, of the individual behavior towards the medicament,the nature of its formulation and the point in time, or interval, atwhich the medicament is administered. For instance, it may suffice insome cases to make do with less than the previously mentioned minimumamount, while in other cases the upper limit specified must be exceeded.In the case where relatively large amounts are administered, it may beadvisable to divide the latter into several individual doses taken overone day.

Starting compounds EXAMPLE I

3,5-Difluorophenylhydrazine ##STR13##

30.50 g (2.363 mmol) of 3,5-difluoroaniline are suspended in 128 ml (700mmol) of 20% strength HCl, and the suspension is stirred with 16.46 g(236.3 mmol) of sodium nitrite in 95 ml of water at temperatures ofbelow 5° C. The mixture is then stirred for 30 minutes at 0° C. so thatthe solid dissolves almost completely. The cold solution is added inportions to 769 g (2.95 mol) of a 40% strength sodium bisulphitesolution with cooling, the mixture being maintained at a pH of 6.5 with2N sodium hydroxide solution. The mixture is now refluxed for 4 hours,the pH of 6.5 being checked every 30 minutes and, if appropriate,readjusted. After cooling, the mixture is rendered alkaline using 1Nsodium hydroxide solution and extracted 5 times using 400 ml of CH₂ Cl₂each time, the extract is dried using Na₂ SO.sub. 4 and the solvent isevaporated off, and the residue is stirred with petroleum ether anddried in a high vacuum.

Yield: 17.34 g (120.3 mmol; 51% of theory) M.p.: 93°-95° C. R_(f) =0.9(ethyl acetate)

EXAMPLE II

3-(4-Chlorophenylsulphonamido)-5,7-difluoro-1,2,3,4-tetrahydrocarbazole##STR14##

14.0 g (97 mmol) of the compound of Example I and 27.95 g (97 mmol) of4-chloro-N-(4-oxo-cyclohexyl)-benzenesulphonamide are refluxed for 5hours in 190 ml of ethanol and 36 ml of concentrated sulphuric acid,then the mixture is cooled and diluted with 300 ml of water. The mixtureis extracted 4 times using 250 ml of ethyl acetate each time, and theorganic phase is dried using sodium sulphate, filtered with suction overkieselguhr and evaporated. The residue is stirred with methylenechloride and dried in a high vacuum.

Yield: 37.6 g (95 mmol; 98% of theory) M.p.: 171°-174° C.

EXAMPLE III

3-(4-Chlorophenylsulphonamido)-9-(2-cyanoethyl)-5,7-difluoro-1,2,3,4-tetrahydrocarbazole##STR15##

5.95 g (15.0 mmol) of the compound from Example II are dissolved underargon in 30 ml of dimethylformamid, analytical grade, and 495 mg (16.5mmol) of 80% sodium hydride in paraffin oil are added at roomtemperature with stirring. When the evolution of hydrogen has ceased,1.75 g. (33.0 mmol) of acrylonitrile are added and the mixture isstirred for 30 minutes. If the starting material has not disappearedcompletely (TLC check/toluene: ethyl acetate=4:1), another 0.23 g (4.3mmol) of acrylonitrile are added and the mixture is again stirred for 30minutes. 50 ml of ethyl acetate are added, and the mixture is shaken 3times using 50 ml of 1N sulphuric acid each time, and the organic phaseis dried using sodium sulphate and evaporated. The residue ischromatographed on Silica gel 60 (Merck/particle size 40-63 μm/eluentfirst toluene, then increasing proportions of ethyl acetate, ending withpure ethyl acetate).

Yield: 4.50 g (10.0 mmol; 67l of theory) M.p.: 114°-117° C. R_(f) =0.24(toluene/ethyl acetate=4:1)

Preparation Example (Formula I) EXAMPLE 1

3-(4-Chlorophenylsulphonamido)-9-(2-carboxyethyl)-5,7-difluoro-1,2,3,4-tetrahydrocarbazole##STR16##

3.05 g (6.8 mmol) of the compound from Example III are dissolved in 20ml of ethanol, 100 ml of 10% strength sodium hydroxide solution areadded, and the mixture is then stirred under reflux for 16 hours. Thecooled batch is extracted by shaking twice using 50 ml of methylenechloride each time, and a pH of 1 is established at 0° C., using 6Nhydrochloric acid. The precipitate which has separated out is filteredoff with suction, washed with water to neutrality, dried in a highvacuum over phosphorus pentoxide and sodium hydroxide, and weighed.

Yield: 2.73 g (5.8 mmol; 86% of theory) M.p.: 134° C.

The compounds listed in Table 1 can be prepared analogously, using theprocedure for Example 1:

                  TABLE 1                                                         ______________________________________                                         ##STR17##                                                                    Example No. R.sup.1                                                                              R.sup.2                                                                              R.sup.3                                                                            R.sup.4                                                                            X   R.sub.f value*                        ______________________________________                                        2           F      H      F    H    F   0.33                                  3           H      F      H    F    F   0.39                                  4           H      F      H    F    Cl  0.31                                  ______________________________________                                         *Mobile phase: dichloromethane/methanol = 10:1                           

EXAMPLE 5

3-(4-Chlorophenylsulphonamido)-9-(2-ethoxycarbonylmethyl)-1,2,3,4-tetrahydrocarbazole##STR18##

6.2 g (21.5 mmol) of 4-chloro-N-(4-oxo-cyclohexyl)-benzenesulphonamideand 4.2 g (21.5 mmol) of (1-phenylhydrazine) acetic acid ethyl ester arerefluxed for 6 hours in 30 ml of ethanol and 5 ml of concentratedsulphuric acid. After the mixture has cooled, 70 ml of water are addedand the mixture is extracted 5 times using 40 ml of ethyl acetate eachtime. The organic phase is dried using sodium sulphate and evaporated.The crude product is purified by chromatography on Silica gel 60(Merck/particle size 63-200 μm), using methylene chloride as the mobilephase.

Yield: 5.1 g (11.4 mmol; 53% of theory) M.p.: 64°-66° C. R_(f) =0.45(dichloromethane)

EXAMPLE 6

3-(4-Chlorophenylsulphonamido)-9-(2-carboxymethyl)-1,2,3,4-tetrahydrocarbazole##STR19##

3.5 g (7.8 mmol) of the compound from Example 5 are dissolved in 30 mlof ethanol, 16 ml of 1N sodium hydroxide solution are added, and themixture is stirred at room temperature for 2 hours. The solvent isevaporated off, the residue is taken up in 50 ml of water, and themixture is extracted twice using 20 ml of methylene chloride each time.After the mixture has been acidified using 2N sulphuric acid (pH=1), itis extracted 3 times using 30 ml of ethyl acetate each time, thecombined organic phases are dried using sodium sulphate, and the solventmixture is evaporated off. The resulting foam, which solidifies in ahigh vacuum, is soluble in ether, from which it reprecipitates onscratching.

Yield: 2.32 g (5.5 mmol/71% of theory) Melting point: 172°-174° C.

EXAMPLE 7

3-(4-Chlorophenylsulphonamido)-6-fluoro-9-(2-methoxycarbonylethyl)-1,2,3,4-tetrahydrocarbazole##STR20##

2.5 g (5.55 mmol) of3-(4-chlorophenylsulphonamido)-6-fluoro-9-(2-carboxyethyl)-1,2,3,4-tetrahydrocarbazoleare treated with 50 ml of absolute methanol and 1 ml of concentratedsulphuric acid. The mixture is stirred at reflux temperature for 2 hoursand concentrated on a rotary evaporator. The crystalline residueobtained on evaporation is stirred with ether, the solids are filteredoff with suction and then recrystallized from methanol. This gives 2.0 gof colorless crystals (77.5% of theory).

Melting point: 143° C. Thin-layer chromatography in the mobile phasesystem toluene/ethanol=6:1 R_(f) =0.23

The examples listed in Table 2 were prepared analogously to Example 7:

                  TABLE 2                                                         ______________________________________                                         ##STR21##                                                                                                      Melting point/                              Example No.                                                                             R.sup.2                                                                             Y             X   R.sub.f value*                              ______________________________________                                        8         F     OC.sub.2 H.sub.5                                                                            Cl  122° C..sup.a)                       9         F     OCH(CH.sub.3).sub.2                                                                         Cl  152° C..sup.b)                       10        H     OC.sub.3 H.sub.7 -i                                                                         F   0.54.sup.a)                                 11        H     OC.sub.2 H.sub.5                                                                            F   0.52.sup.a)                                 12        H     OCH.sub.3     F   0.52.sup.a)                                 ______________________________________                                         R.sub.f values*                                                               Mobile phase systems:                                                         .sup.a) toluene/ethanol (6:1)                                                 .sup.b) toluene/ethanol (10:1)                                           

Merck TLC aluminum roll, Silica gel 60, code No. 5562

EXAMPLE 13

3-(4-Fluorophenylsulphonamido)-9-(2-carbamoylethyl)-1,2,3,4-tetrahydrocarbazole##STR22##

1 g (2.18 mmol) of the compound from Example 11 is treated with 20 ml ofa 6N ammonia solution in methanol, and the mixture is allowed to standfor 3 days at room temperature. It is then concentrated, and the residueis purified by flash chromatography in the mobile phase systemtoluene/ethyl acetate (3:1, 1:1) and then in the mobile phase systemtoluene/ethanol (10:1, 5:1) using a column packed with 40 g of Silicagel 60. The fractions are concentrated, and a colorless foam isobtained.

Yield: 0.52 g (55.9% of theory) R_(f) value=0.26 (toluene/ethanol 6:1,Merck TLC aluminum roll, Silica gel 60 code No. 5562).

The compounds listed in Table 3 were prepared from the correspondingesters in analogy with the procedure of Example 13:

                  TABLE 3                                                         ______________________________________                                         ##STR23##                                                                    Example No.  Y         Melting point (°C.)                             ______________________________________                                        14           N(CH.sub.3).sub.2                                                                       224                                                    15           NH.sub.2  214                                                    ______________________________________                                    

EXAMPLE 16

3-(R)-(4-Fluorophenylsulphonamido)-9-[2-(N-phenylsulphonecarbamoyl)-ethyl]-1,2,3,4-tetrahydrocarbazole##STR24##

4.16 g (10.0 mmol) of(R)-3-(4-fluorophenylsulphonamido)-9-(2-carboxyethyl)-1,2,3,4-tetrahydrocarbazoleare dissolved in 70 ml of methylene chloride, analytical grade, and thesolution is treated with 1.58 g (10 mmol) of benzene sulphonamide. 2 mlof dimethylformamide together with 2.3 g (12.0 mmol) ofN-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in 25 ml ofmethylene chloride and 1.7 ml (12 mmol) of triethylamine are then addedto dissolve, and the mixture is stirred for 24 hours at roomtemperature. The reaction mixture is washed twice using 40 ml of 2Nsulphuric acid each time, once using 50 ml of saturated sodiumbicarbonate solution and once using saturated sodium chloride solution,dried over sodium sulphate, concentrated and freed from residual solventin a high vacuum. Column chromatography (Merck Silica gel, 40-60μm/methylene chloride: methanol=15:1) gives 2.56 g (4.6 mmol) ofproduct. R_(f) =0.62 (methylene chloride/methanol=10:1)

The examples listed in Table 4 are prepared analogously to the procedureof Example 16:

                  TABLE 4                                                         ______________________________________                                         ##STR25##                                                                    Example No.                                                                             R            R.sub.f Mobile phase                                   ______________________________________                                        17        CH.sub.3     0.45    Toluene/acetone 4:1                            18                                                                                       ##STR26##   0.29    Toluene/acetone 3:1                            ______________________________________                                    

The examples listed in Table 5 are prepared analogously to the procedureof Example 6.

                  TABLE 5                                                         ______________________________________                                         ##STR27##                                                                    Example No. m     R.sub.f  Mobile phase                                       ______________________________________                                        19          3     0,49     Dichlormethane/methanol                                                       10:1                                               20          4     0,66     Ethylacetate                                       ______________________________________                                    

It will be appreciated that the instant specification is set forth byway of illustration and not limitation, and that various modificationsand changes may be made without departing from the spirit and scope ofthe present invention.

What is claimed is:
 1. A substituted cycloalkano[b]dihydroindole- orindole-sulphonamide of the formula ##STR28## in which R¹, R², R³, R⁴ asidentical or different and represent hydrogen or fluorine provided thatat least two of these substituents are fluorine, andm represents 1, 2, 3or 4or salt thereof.
 2. A compound according to claim 1, wherein suchcompound is3-(4-chlorophenylsulphonamido)-9-(2-carboxyethyl)-5,7-difluoro-1,2,3,4-tetrahydrocarbazoleof the formula ##STR29## or a salt thereof.
 3. A compound according toclaim 1, wherein such compound is3-(4-chlorophenylsulphonamido)-9-(2-carboxyethyl)-6,8-difluoro-1,2,3,4-tetrahydrocarbazoleof the formula ##STR30## or a salt thereof.
 4. A composition for thetreatment of thromboses, thromboembolisms, ischaemias, asthma andallergies, and for the prophylaxis of myocardia infarct comprising anamount effective therefor of a compound or salt thereof according toclaim 1 and a pharmacologically acceptable diluent.
 5. The method oftreating thromboses, thromboembolisms, ischaemias, asthma and allergies,and for the prophylaxis of myocardial infarct in a patient in needthereof which comprises administering to such patient an amounteffective therefor of a compound or salt thereof according to claim 1.6. The method according to claim 3, wherein such compoundis3-(4-chlorophenylsulphonamido)-9-(2-carboxyethyl)-5,7-difluoro-1,2,3,4-tetrahydrocarbazole,or3-(4-chlorophenylsulphonamido)-9-(2-carboxyethyl)-6,8-difluoro-1,2,3,4-tetrahydrocarbazole,ora salt thereof.